bims-mideyd Biomed News
on Mitochondrial dysfunction in eye diseases
Issue of 2026–06–21
five papers selected by
Rajalekshmy “Raji” Shyam, University of Iowa
  1. Interdependent roles of PKM2 in photoreceptors and RPE: implications for retinal degeneration.
  2. Linking Neurodegeneration and Age-related Macular Degeneration: Unified Pathways and Intervention Strategies.
  3. TREM2 restrains myeloid inflammasome activation to protect against photoreceptor degeneration.
  4. Single-cell and spatial analyses reveal endothelial-macrophage inflammatory crosstalk in dry age-related macular degeneration.
  5. Thapsigargin-induced autophagic flux impairment and inflammation are potentiated by CLN3 deficiency and alleviated by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) in human ARPE-19 cells.
  1. Cell Death Dis. 2026 Jun 19.
    Interdependent roles of PKM2 in photoreceptors and RPE: implications for retinal degeneration.
    Ammaji Rajala, Rahul Rajala, Larissa J Trevino, Tyler M Black, Gennadiy Moiseyev, Michael Kinter, Raju V S Rajala.
      Pyruvate kinase M2 (PKM2) functions as both a glycolytic enzyme and a transcriptional co-activator that coordinates metabolism and cell survival. Here, we define the developmental timing, cellular distribution, and physiological role of PKM isoforms in the mouse retina. PKM2 expression begins at postnatal day 2, preceding PKM1, and is highly enriched in photoreceptors, whereas PKM1 predominates in retinal ganglion cells. Conditional deletion of PKM2 in the retina, rods, or retinal pigment epithelium (RPE) demonstrated that PKM2 is essential for maintaining retinal structure and function. Loss of PKM2 impaired glycolytic activity, decreased ATP generation, and disrupted metabolic balance, leading to cellular disorganization and degeneration in both photoreceptors and the RPE. In the RPE, PKM2 deficiency decreased RPE65 protein levels and impaired the regeneration of 11-cis-retinal, disrupting the visual cycle. PKM2 deletion disrupted the normal cone opsin gradient, indicating that PKM2-dependent metabolic and transcriptional functions are essential for maintaining proper cone organization in the retina. Moreover, rod-specific deletion of PKM2 in Abca4 mutant mice showed early signs of retinal degeneration. The studies described in this manuscript highlight the interdependence of photoreceptor and RPE metabolism and show that PKM2 plays an important role in retinal energy homeostasis and neuronal survival, providing insight into the mechanisms underlying photoreceptor and RPE degeneration in age-related macular degeneration.
    DOI:  https://doi.org/10.1038/s41419-026-08997-3
  2. CNS Neurol Disord Drug Targets. 2026 Jun 12.
    Linking Neurodegeneration and Age-related Macular Degeneration: Unified Pathways and Intervention Strategies.
    Shubhangi Mukherjee, Suman Kumar Ray, Sukhes Mukherjee.
      Age-related macular degeneration (AMD) is caused by the degeneration of photoreceptors and retinal pigment epithelium (RPE) along with drusen deposition and is the leading cause of vision loss in older adults. Both these structures within the central nervous system (CNS) utilize common neuro-inflammatory mechanisms because the retina is an outgrowth of the brain. Like the brain, the eye has its own physical characteristics and surface molecules as well as a tendency towards specific immune reactions. Numerous distinct neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Frontotemporal dementia (FTD) that impact the brain present as eye symptoms, and the conventional diagnosis of these neurodegenerative disorders (NDs) is often preceded by ocular symptoms. Furthermore, several eye-specific disorders have characteristics in common with other CNS disorders. NDs and AMD share common key features, such as tau and amyloid-β deposits, oxidative stress response, chronic inflammation, and dysregulation of microglia and müller glia. Common pathological mechanisms include complement activation, amyloid aggregation, neuroinflammation, vascular impairment, and cell death, providing a basis for a convergent neuroimmune axis between retinal and cerebral degeneration. Comparing these age-related diseases will facilitate the identification of shared risk factors, convergent molecular pathways, and potential cross-applicable therapeutic strategies, such as anti-inflammatory, anti-complementary, anti-apoptotic, and anti-VEGF-based approaches. This knowledge may enhance understanding of neurodegenerative diseases, help identify early biomarker development for diagnosis, and enable the design of targeted therapeutic strategies.
    Keywords:  Age-related macular degeneration (AMD); amyloid β aggregation.; neurodegenerative disorders (NDs); neuroinflammation; pathophysiological mechanism; targeted therapy
    DOI:  https://doi.org/10.2174/0118715273450093260523224914
  3. J Neuroinflammation. 2026 Jun 13.
    TREM2 restrains myeloid inflammasome activation to protect against photoreceptor degeneration.
    Tianxi Wang, Liyun Su, Manon Szczepan, Xingyan Wang, Austin T Gregg, Jessica Guo, Lois E H Smith, Ye Sun.
      Myeloid cells, including infiltrating macrophages and resident microglia, are critical regulators of retinal homeostasis and respond rapidly to photoreceptor stress. Dysregulated myeloid responses, however, can exacerbate retinal degeneration. Triggering receptor expressed on myeloid cells 2 (TREM2) modulates phagocytosis, metabolism, and inflammatory signaling, yet its role in retinal degeneration remains incompletely understood. Here, we investigated TREM2 function in the retinal degeneration 10 (rd10) mouse model of inherited retinal degeneration, characterized by progressive photoreceptor loss and robust myeloid cell activation. TREM2 expression was upregulated in degenerating retinas, and global TREM2-deficiency in rd10 mice exhibited accelerated photoreceptor cell death, reduced outer nuclear layer thickness, disrupted retinal pigment epithelium integrity, and altered microglial spatial dynamics. Single-cell transcriptomics revealed that TREM2-positive microglia express APOE-associated and interferon-primed programs. Global TREM2 deficiency was associated with increased inflammasome-related signaling in retinal myeloid cells, including elevated cleaved caspase-1, cleaved gasdermin D, and mature interleukin-1β, linking amplified immune priming to pyroptotic signaling. Genetic or pharmacological inhibition of gasdermin D significantly mitigated photoreceptor loss in global TREM2-deficient rd10 retinas, demonstrating a functional contribution of inflammasome-associated responses to disease exacerbation. Together, these findings support a protective role for TREM2-associated immune regulation in the degenerating retina and identify downstream inflammasome pathways as potential therapeutic targets in retinal degenerative diseases.
    Keywords:  Gasdermin D; Inflammasome Activation; Myeloid Cells; Myeloid Pyroptosis; Photoreceptors; Retinal Degeneration; TREM2
    DOI:  https://doi.org/10.1186/s12974-026-03903-2
  4. J Transl Med. 2026 Jun 16. pii: 793. [Epub ahead of print]24(1):
    Single-cell and spatial analyses reveal endothelial-macrophage inflammatory crosstalk in dry age-related macular degeneration.
    Yujie Chen, Chuling Liu, Jinghan Chen, Yimin Huang, Guiping Pan, Pan Wang, Yishan Hu, Lin Chen, Yuxi Zhang, Yan Wang.
       BACKGROUND: Dry age-related macular degeneration (AMD) is characterized by progressive degeneration of the retinal pigment epithelium-choroid interface, accompanied by immune dysregulation. However, the cellular interactions and regulatory mechanisms driving macrophage activation in this process remain incompletely understood.
    METHODS: We integrated spatial transcriptomics and single-cell RNA sequencing data from a photo-oxidative damage mouse model and human dry AMD samples. A series of bioinformatic analyses, including cell-cell communication analysis, enrichment analysis, and pseudotime trajectory analysis, were performed to characterize cellular features and regulatory pathways.
    RESULTS: In the photo-oxidative damage mouse model, the RPE-choroid region showed marked infiltration of myeloid cells. In human dry AMD samples, SLC16A10-positive macrophages were enriched and exhibited pro-inflammatory features. Further analysis revealed that endothelial cells regulate SLC16A10-positive macrophages through the TNFSF10-TNFRSF10B pathway, with NFKB1 acting as a key regulator to activate NF-κB signaling, thereby promoting the formation of a vascular-immune inflammatory niche.
    CONCLUSIONS: This study systematically characterizes immune remodeling in the RPE-choroid region in dry AMD and identifies an endothelial-macrophage TNFSF10-TNFRSF10B-NF-κB signaling pathway that drives disease progression. These findings provide new insights into disease mechanisms and suggest potential therapeutic targets for dry AMD.
    Keywords:  Age-related macular degeneration; Dry AMD; Macrophages; Single-cell RNA sequencing; Spatial transcriptomics; TNFSF10–TNFRSF10B signaling
    DOI:  https://doi.org/10.1186/s12967-026-08393-7
  5. Biochem Biophys Res Commun. 2026 Jun 16. pii: S0006-291X(26)00921-6. [Epub ahead of print]829 154157
    Thapsigargin-induced autophagic flux impairment and inflammation are potentiated by CLN3 deficiency and alleviated by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) in human ARPE-19 cells.
    Tommi Torsti, Maria Hytti, Maija Toppila, Markus M Forsberg, Anu Kauppinen.
      Juvenile neuronal lipofuscinosis (JNCL) is a rare disease caused by mutations in the CLN3 gene. It leads to early vision loss mediated by retinal degeneration. Impaired autophagosomal-lysosomal degradation is a major hallmark of JNCL pathology, and neuroinflammation has also been postulated to play a role in its pathogenesis. Thapsigargin, a selective inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase, inhibits autophagy, leading to an accumulation of autophagosomes/autophagophores in cells. Cells with defective CLN3 protein function have been found to be particularly sensitive to the anti-autophagic effects of thapsigargin. Here, we characterized the effects of thapsigargin on inflammatory cytokines and autophagic markers in ARPE-19 cells using ELISA and western blotting. We further examined these effects in cells deficient in CLN3 function by exposing the cells to CLN3 siRNA and testing whether the effects of thapsigargin could be modulated by the well-known autophagy activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). Thapsigargin induced the accumulation of LC3 and p62/SQSTM1, consistent with impaired autophagic flux in ARPE-19 cells. Additionally, we observed that thapsigargin possessed pro-inflammatory potential, as it induced the release of IL-6 in ARPE-19 cells, no inflammasome activation was detected. Both effects were enhanced by CLN3 siRNA and alleviated by AICAR. In conclusion, thapsigargin-induced impaired autophagic flux and the accompanying inflammatory response are more pronounced in CLN3-deficient ARPE-19 cells, indicating that loss of CLN3 function affects both autophagy and inflammatory signaling.
    Keywords:  Autophagy; CLN3; Inflammation; Lysosomal storage disease; Retinal pigment epithelium
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154157
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